OBJECTIVES: We sought to prioritize interventions for increasing human papillomavirus (HPV) vaccination coverage based on cost-effectiveness from a US state perspective to inform decisions by policy makers. METHODS: We developed a dynamic simulation model of HPV transmission and progression scaled to a medium-sized US state (5 million individuals). We modeled outcomes over 50 years comparing no intervention to a one-year implementation of centralized reminder and recall for HPV vaccination, school-located HPV vaccination, or quality improvement (QI) visits to primary care clinics. We used probabilistic sensitivity analysis to assess a range of plausible outcomes associated with each intervention. Cost-effectiveness was evaluated relative to a conservative willingness-to-pay threshold; $50 000 per quality-adjusted life-year (QALY) . RESULTS: All interventions were cost-effective, relative to no intervention. QI visits had the lowest cost and cost per QALY gained ($1538 versus no intervention). Statewide implementation of centralized reminder and recall cost $28 289 per QALY gained versus QI visits. School-located vaccination had the highest cost but was cost-effective at $18 337 per QALY gained versus QI visits. Scaling to the US population, interventions could avert 3000 to 14 000 future HPV cancers. When varying intervention cost and impact over feasible ranges, interventions were typically preferred to no intervention, but cost-effectiveness varied between intervention strategies. CONCLUSIONS: Three interventions for increasing HPV vaccine coverage were cost-effective and offered substantial health benefits. Policy makers seeking to increase HPV vaccination should, at minimum, dedicate additional funding for QI visits, which are consistently effective at low cost and may additionally consider more resource-intensive interventions (reminder and recall or school-located vaccination).